Exploiting PI3K Pathway Inhibitor Therapy in Prostate Cancer

分子靶向癌症治疗评估中的一个限速步骤是匹配 正确的抑制剂与正确的患者。成功需要患者和患者的肿瘤组织的分子图谱 预测对特定药物敏感性的生物标记物的发现。该项目在 前列腺癌，重点是PI3-激酶(PI3K)途径的抑制剂。这个项目是在进展的基础上发展起来的 Sawyers博士和Wu博士在资助的前5年研究mTOR抑制剂，并利用他们的 开发基因工程前列腺小鼠模型并使用这些模型评估的专业知识 信号通路抑制剂。由于这个项目中的概念显然已经成熟，可以用于临床翻译，我们 将索耶斯博士最近搬迁到纪念斯隆-凯特琳癌症中心(MSKCC)视为一项资产， 提供接触由Howard Scher博士和Peter博士指导的杰出临床前列腺癌小组的机会 斯卡迪诺，这将补充加州大学洛杉矶分校的临床项目。该项目将使用三个特点良好的 基因工程前列腺癌模型(PTEN，MYC，AKT)：(I)定义和测量通路- 用小鼠模型和人类研究肿瘤组织和血清中的前列腺癌生物标志物 患者和(Ii)使用激素单独和联合使用PIS途径抑制剂治疗进行评估。 依赖和激素耐药前列腺癌小鼠模型。这些发现将指导设计和 PI3激酶途径抑制剂在前列腺癌中的新辅助临床试验 MSKCC和UCLA，并评估循环肿瘤细胞(CTCs)作为肿瘤基因组读数在 前列腺癌患者。

A rate-limiting step in the evaluation of molecularly targeted cancer therapeutics is the ability to match the right inhibitor with the right patient. Success requires molecularly profiling of tumor tissue from patients and the discovery of biomarkers that predict sensitivity to specific agents. This project addresses this question in prostate cancer with the focus on inhibitors of the PI3-kinase (PI3K) pathway. The project builds on progress by Drs. Sawyers and Wu during the first 5 years of funding studying mTOR inhibitors and capitalizes on their expertise in developing genetically engineered prostate mouse models and using these models to evaluate signaling pathway inhibitors. Because the concepts in this project are clearly ripe for clinical translation, we view Dr. Sawyers' recent relocation to Memorial Sloan-Kettering Cancer Center (MSKCC) as an asset, providing access to an outstanding clinical prostate cancer group directed by Drs. Howard Scher and Peter Scardino, that will complement the clinical program at UCLA. The project will use three well-characterized genetically engineered prostate cancer models (PTEN, MYC, AKT) to: (i) define and measure pathway- specific, prostate cancer biomarker signatures in tumor tissue and serum using mouse models and human patients and (ii) evaluate PIS kinase pathway inhibitor therapy alone and in combination using hormone- dependent and hormone refractory prostate cancer mouse models. These findings will guide the design and execution of neoadjuvant clinical trials of PI3 kinase pathway inhibitors in prostate cancer, collaboratively at MSKCC and UCLA, and assess the utility of circulating tumor cells (CTCs) as oncogenomic readouts in prostate cancer patients.